Ruxolitinib (Jakafi, Jakavi, Incyte, Novartis) is a cyclopentylproprionitrile derivative tyrosine kinase inhibitor (TKI) that targets with high selectivity a new class of tyrosine kinases represented by JAK1 and JAK2, which are inhibited at IC50 of 3.3 and 2.8 nM, respectively. Lower activity is expressed by this drug on TYK2 (19 nM), and much lower on JAK3 (428 nM). In fact, this TKI was designed to spare JAK3 to avoid impairing lymphopoiesis. In 2011, the Food and Drug Administration (FDA) granted approval for the treatment of intermediate-2 or high-risk myelofibrosis (MF), primary myeloproliferative disorder (PMF), post-polycythemia vera myelofibrosis (PPVMF), and post-essential thrombocytopenia myelofibrosis (PETMF). The European Medicines Agency (EMA) approved ruxolitinib in 2012 for the treatment of disease-related splenomegaly, or symptoms in adult patients with PMF, PPVMF, or PETMF. Subsequently, the FDA (December 2014) and EMA (January 2015) extended the treatment to polycythemia vera patients, after an inadequate response or intolerance to hydroxyurea. The initial safety profile in MF patients was based on 301 exposed patients in Phase III INCB-351 and INCB-352 trials. The integrated database consisted of 617 patients (455 with MF) exposed to ruxolitinib, most of whom had been unsuccessful with other therapies. The safety profile is characterized by myelosuppression, mainly expressed as thrombocytopenia, anemia, and neutropenia; and nonhematologic events, such as cephalea, dizziness, and bruising. Other events of relevance are immunosuppression, as manifested by the increased frequency of infections, including tuberculosis, viral infections and reactivations, opportunistic infections, and progressive multifocal leukoencephalopathy; risk of nonmelanoma skin cancer, lipase elevation, and the ruxolitinib withdrawal syndrome consisting of symptomatic disease exacerbation expressed as acute respiratory distress syndrome, pyrexia, hypotension, disseminated intravascular coagulation, and multiorgan failure.